Letter abstract
Nature Genetics 39, 1397 - 1402 (2007)
Published online: 14 October 2007 | doi:10.1038/ng.2007.8
Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis
Massimo M Santoro1,2, Temesgen Samuel3,4, Tracy Mitchell1,5, John C Reed3 & Didier Y R Stainier1
Integrity of the blood vessel wall is essential for vascular homeostasis and organ function1, 2. A dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathological angiogenesis3, 4, 5, 6. The genetic and molecular mechanisms regulating these processes in vivo are still largely unknown. Here, we show that Birc2 (also known as cIap1) is essential for maintaining endothelial cell survival and blood vessel homeostasis during vascular development. Using a forward-genetic approach, we identified a zebrafish null mutant for birc2, which shows severe hemorrhage and vascular regression due to endothelial cell integrity defects and apoptosis. Using genetic and molecular approaches, we show that Birc2 positively regulates the formation of the TNF receptor complex I in endothelial cells, thereby promoting NF-
B activation and maintaining vessel integrity and stabilization. In the absence of Birc2, a caspase-8–dependent apoptotic program takes place that leads to vessel regression. Our findings identify Birc2 and TNF signaling components as critical regulators of vascular integrity and endothelial cell survival, thereby providing an additional target pathway for the control of angiogenesis and blood vessel homeostasis during embryogenesis, regeneration and tumorigenesis.
- Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94158, USA.
- Department of Environmental and Life Sciences, University of Piemonte Orientale "A. Avogadro", Alessandria, 15100, Italy.
- Burnham Institute for Medical Research, La Jolla, California 92037, USA.
- Tuskegee University, College of Veterinary Medicine, Nursing and Allied Health, Pathobiology, Pattersen Hall, Tuskegee, Alabama 36088, USA.
- Osteoarthritis Research Group, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
Correspondence to: Massimo M Santoro1,2 e-mail: massimo.santoro@ucsf.edu
Correspondence to: Didier Y R Stainier1 e-mail: didier.stainier@biochem.ucsf.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesisNature Cell Biology Letter (01 Nov 2008)
The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular systemNature Article (11 Nov 2004)
MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundaryNature Neuroscience Article (01 Jun 2008)
Notch signalling limits angiogenic cell behaviour in developing zebrafish arteriesNature Letters to Editor (15 Feb 2007)
Mesodermal Wnt2b signalling positively regulates liver specificationNature Letters to Editor (10 Aug 2006)
